Cells respond to extracellular stimuli by activating signal transduction pathways, which culminate in gene expression. A critical component of eukaryotic signal transduction is the activation of protein kinases, which phosphorylate a host of cellular substrates. Certain protein serine/threonine kinases transduce signals to the nucleus of cells in response to cellular stresses. These kinases are known as stress-activated protein kinases (SAPKs), or, alternately, c-Jun N-terminal (amino-terminal kinases (JNKs), and likely play a role in the genetic response of many components of the cardiovascular system to disease processes [Force, et al., Circulation Research, 78(6): 947-953 (1996)]. Stress-activated protein kinases activate genes responsible for apoptosis (cell death); SAPK activation precedes the onset of apoptosis.
Surprisingly, it has been found that carvedilol, a dual non-selective .beta.-adrenoceptor and .alpha..sub.1 -adrenoceptor antagonist, inhibits stress-activated protein kinases. This inhibition means that carvedilol and related Formula I compounds are useful in treating diseases mediated by stress-activated protein kinases. Importantly, this inhibition means that carvedilol and related Formula I compounds are useful for treating SAPK-initiated apoptosis. This inhibition also means that carvedilol and related Formula I compounds are useful for treating cardiovascular diseases, such as ischemia, atherosclerosis, heart failure, and restenosis.